Feng Bo, Yao Pin Mei, Li Yankun, Devlin Cecilia M, Zhang Dajun, Harding Heather P, Sweeney Michele, Rong James X, Kuriakose George, Fisher Edward A, Marks Andrew R, Ron David, Tabas Ira
Department of Medicine, Columbia University, New York, NY 10032, USA.
Nat Cell Biol. 2003 Sep;5(9):781-92. doi: 10.1038/ncb1035. Epub 2003 Aug 10.
Excess cellular cholesterol induces apoptosis in macrophages, an event likely to promote progression of atherosclerosis. The cellular mechanism of cholesterol-induced apoptosis is unknown but had previously been thought to involve the plasma membrane. Here we report that the unfolded protein response (UPR) in the endoplasmic reticulum is activated in cholesterol-loaded macrophages, resulting in expression of the cell death effector CHOP. Cholesterol loading depletes endoplasmic reticulum calcium stores, an event known to induce the UPR. Furthermore, endoplasmic reticulum calcium depletion, the UPR, caspase-3 activation and apoptosis are markedly inhibited by selective inhibition of cholesterol trafficking to the endoplasmic reticulum, and Chop-/- macrophages are protected from cholesterol-induced apoptosis. We propose that cholesterol trafficking to endoplasmic reticulum membranes, resulting in activation of the CHOP arm of the UPR, is the key signalling step in cholesterol-induced apoptosis in macrophages.
细胞内过量的胆固醇会诱导巨噬细胞凋亡，这一事件可能会促进动脉粥样硬化的发展。胆固醇诱导凋亡的细胞机制尚不清楚，但此前人们认为它涉及质膜。在此我们报告，内质网中的未折叠蛋白反应（UPR）在胆固醇负载的巨噬细胞中被激活，导致细胞死亡效应因子CHOP的表达。胆固醇负载会耗尽内质网钙储存，这是已知的诱导UPR的事件。此外，通过选择性抑制胆固醇向内质网的转运，内质网钙耗竭、UPR、半胱天冬酶-3激活和凋亡均受到显著抑制，并且Chop-/-巨噬细胞可免受胆固醇诱导的凋亡。我们提出，胆固醇向内质网膜的转运导致UPR的CHOP臂被激活，这是巨噬细胞中胆固醇诱导凋亡的关键信号步骤。
